This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. At least five arenaviruses cause viral hemorrhagic fevers in humans. Lassa virus, an Old World arenavirus, utilizes the cellular receptor a-dystroglycan to infect cells1. Machupo, Guanarito, Junin, and Sabia viruses are New World hemorrhagic fever viruses that do not use a-dystroglycan2. Here we demonstrate a specific, high-affinity association between transferrin receptor 1 (TfR1) and the entry glycoprotein (GP) of Machupo virus. Expression of human TfR1, but not human transferrin receptor 2, in hamster cell lines markedly enhanced infection of viruses pseudotyped with the GP of Machupo and Junin viruses, but not Lassa or lymphocytic choriomeningitis viruses. An anti-TfR1 antibody efficiently inhibited replication of Machupo, Guanarito, Junin, and Sabia viruses, but not that of Lassa virus. Iron depletion of culture media enhanced, and iron supplementation reduced, the efficiency of infection by Junin and Machupo but not Lassa pseudoviruses. These data indicate that TfR1 is a cellular receptor for New World hemorrhagic fever arenaviruses.